Is CLEC2B p.Tyr125Ser (c.374A>C) pathogenic?

CLEC2B p.Tyr125Ser (c.374A>C) is classified Uncertain significance in CLEC2B (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-06). AlphaMissense: likely pathogenic (0.8563); Absent from gnomAD v4.1.

How common is CLEC2B p.Tyr125Ser (c.374A>C) in the general population?

CLEC2B p.Tyr125Ser (c.374A>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CLEC2B p.Tyr125Ser (c.374A>C)?

AlphaMissense predicts likely pathogenic (score 0.8563) — an in-silico prediction, not a clinical call.

CLEC2B p.Tyr125Ser

c.374A>C · VCV4003546

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8563 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.8563	likely pathogenic
REVEL	0.164	moderately benign-leaning
SaProt	LLR -11.96	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.8	GERP 0.61, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 9,268 bp · p 0.23 · regional, not allelic
Overall
CADD	22.4	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CLEC2B
Protein: p.Tyr125Ser
Coding: c.374A>C
MANE Select: NM_005127
Type: single nucleotide variant
Location: chr12:9853376 (GRCh38)
Gene constraint: LOEUF 1.404 · pLI 0.52 (gnomAD)
Structure: AlphaFold pLDDT 92.25
Residue 125: a disulfide bond; the c-type lectin domain

Full CLEC2B gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CLEC2B p.Arg145Lys Uncertain significance ★ ⚠ same type
CLEC2B p.Arg147Gly Uncertain significance ★ ⚠ same type
CLEC2B p.Arg84Trp Uncertain significance ★ ⚠ same type
CLEC2B p.Asn100Lys Uncertain significance ★ ⚠ same type
CLEC2B p.Asn44Lys Uncertain significance ★ ⚠ same type
CLEC2B p.Cys123Tyr Uncertain significance ★ ⚠ same type
CLEC2B p.Glu53Gly Uncertain significance ★ ⚠ same type
CLEC2B p.Glu53Val Uncertain significance ★ ⚠ same type

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/clec2b-p-tyr125ser (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown